title: Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor.
abstract: OBJECTIVE
  Parkinson disease (PD) is characterized by striatal dopamine depletion, which explains clinical symptoms such as bradykinesia and rigidity, but not resting tremor. Instead, resting tremor is associated with increased activity in a distinct cerebellothalamic circuit. To date, it remains unknown how the interplay between basal ganglia and the cerebellothalamic circuit can result in resting tremor.
  
  
  METHODS
  We studied 21 tremor-dominant PD patients, 23 nontremor PD patients, and 36 controls. Using functional magnetic resonance imaging, we measured functional connectivity between basal ganglia nuclei (globus pallidus internus [GPi], globus pallidus externus [GPe], putamen, caudate) and the cerebellothalamic circuit. Using electromyography during scanning, we measured tremor-related activity in the basal ganglia and cerebellothalamic circuit. We also quantified striatopallidal dopamine depletion using iodine-123-N-omega-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)tropane [[I-123]FP-CIT] single photon emission computed tomography.
  
  
  RESULTS
  Pallidal (but not striatal) dopamine depletion correlated with clinical tremor severity. The GPi, GPe, and putamen were transiently activated at the onset of tremor episodes, whereas activity in the cerebellothalamic circuit cofluctuated with tremor amplitude. The GPi and putamen of tremor-dominant PD patients had increased functional connectivity with the cerebellothalamic circuit, which was relegated through the motor cortex.
  
  
  CONCLUSIONS
  Resting tremor may result from a pathological interaction between the basal ganglia and the cerebellothalamic circuit. The cerebellothalamic circuit, which controls tremor amplitude, appears to be driven into tremor generation when receiving transient signals from the dopamine-depleted basal ganglia. This may explain why basal ganglia dysfunction is required for developing resting tremor, although a cerebellothalamic circuit produces it. Our model also clarifies why neurosurgical interventions targeted at either the basal ganglia or the cerebellothalamic circuit can both suppress tremor.
authors.affiliation: Donders Institute for Brain, Cognition, and Behavior, Center for Cognitive Neuroimaging, Radboud University Nijmegen, the Netherlands. R.Helmich@neuro.umcn.nl
authors.forename: Rick C
authors.initials: RC
authors.lastname: Helmich
authors.forename: Marcel J R
authors.initials: MJ
authors.lastname: Janssen
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Bastiaan R
authors.initials: BR
authors.lastname: Bloem
authors.forename: Ivan
authors.initials: I
authors.lastname: Toni
mesh_terms: D000704:Analysis of Variance; D001479:Basal Ganglia / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D001931:Brain Mapping; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D013788:Thalamus / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D015899:Tomography, Emission-Computed, Single-Photon; D014202:Tremor / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins